Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4

Rikke B. Holmgaard, Dmitriy Zamarin, David H Munn, Jedd D. Wolchok, James P. Allison

Research output: Contribution to journalArticle

272 Citations (Scopus)

Abstract

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab results in durable responses in metastatic melanoma, though therapeutic benefit has been limited to a fraction of patients. This calls for identification of resistance mechanisms and development of combinatorial strategies. Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. In IDO knockout mice treated with anti-CTLA-4 antibody, we demonstrate a striking delay in B16 melanoma tumor growth and increased overall survival when compared with wild-type mice. This was also observed with antibodies targeting PD-1-PD-L1 and GITR. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.

Original languageEnglish (US)
Pages (from-to)1389-1402
Number of pages14
JournalJournal of Experimental Medicine
Volume210
Issue number7
DOIs
StatePublished - Jul 1 2013

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CTLA-4 Antigen
Indoleamine-Pyrrole 2,3,-Dioxygenase
Immunotherapy
T-Lymphocytes
Neoplasms
Experimental Melanomas
Blocking Antibodies
Antibodies
Regulatory T-Lymphocytes
Immunosuppressive Agents
Knockout Mice
Motivation
Melanoma
Therapeutics
Survival

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. / Holmgaard, Rikke B.; Zamarin, Dmitriy; Munn, David H; Wolchok, Jedd D.; Allison, James P.

In: Journal of Experimental Medicine, Vol. 210, No. 7, 01.07.2013, p. 1389-1402.

Research output: Contribution to journalArticle

Holmgaard, Rikke B. ; Zamarin, Dmitriy ; Munn, David H ; Wolchok, Jedd D. ; Allison, James P. / Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 7. pp. 1389-1402.
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